title: Excited-state dynamics in 6-thioguanosine from the femtosecond to microsecond time scale.
abstract: Patients treated with the immunosuppressant and anticancer drugs 6-thioguanine, azathioprine, or mercaptopurine can metabolize and incorporate them in DNA as 6-thioguanosine. The skin of these patients is sensitive to UVA radiation, and long-term treatment can result in extremely high incidence of sunlight-induced skin cancer. In this contribution the photophysics of 6-thioguanosine have been studied in aqueous buffer solution and in acetonitrile after excitation with UVA light to provide mechanistic insights about the origin of its phototoxicity. It is shown that most of the initial excited-state population in the S(2)(ππ*, L(a)) state decays by ultrafast intersystem crossing to the triplet manifold. A triplet quantum yield of 0.8 ± 0.2 is determined in aqueous buffer solution. A minor fraction of the S(2) population bifurcates on an ultrafast time scale to populate the S(1)(n(S)π*) state, which decays back to the ground state in tens of picoseconds. Quantum-chemical calculations that include solvent effects support the experimental results. The high triplet yield of 6-thioguanosine, which we argue can result in photosensitization of molecular oxygen and photooxidative DNA damage, is proposed to explain the high phototoxicity exhibited by these pro-drugs in patients upon sunlight exposure. Finally, the experimental and computational results for 6-thioguanosine are compared with those reported for the DNA/RNA guanine monomers.
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Reichardt
authors.forename: Cao
authors.initials: C
authors.lastname: Guo
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Crespo-Hernández
mesh_terms: D000042:Absorption; D000097:Acetonitriles / Q000737:chemistry; D002021:Buffers; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004583:Electrons; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D008958:Models, Molecular; D008968:Molecular Conformation; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D012996:Solutions; D013872:Thionucleosides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D013997:Time Factors; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D002021:Buffers; D017319:Photosensitizing Agents; D012996:Solutions; D013872:Thionucleosides; D014867:Water; D006151:Guanosine; D004247:DNA; C005783:6-thioguanosine; C032159:acetonitrile